The incidence of coronary artery disease (CAD) in women is increased in estrogen (E2) deficient states and decreased with postmenopausal E2 replacement. Previous hypotheses to explain this observation are based primarily on indirect effects of E2 on cardiovascular risk factors. Since vascular smooth muscle cell (VSMC) proliferation plays a critical role in the development of CAD, l propose to investigate the hypothesis that steroid sex hormones directly modulate the growth responses of VSMC. Based on preliminary cell culture studies, we provide data demonstrating: (a) the presence of estrogen receptor in human VSMC and (b) an inhibitory effect of E2 on VSMC proliferation. This proposal seeks to pursue three Specific Aims. Specific Aim 1 includes characterization of the abundance, distribution and function of steroid sex hormone receptors in VSMC. Specific Aim 2 involves investigation of the effect of steroid sex hormones on the proliferation of VSMC. Specific Aim 3 is to study the molecular pathways mediating growth-regulatory effects of steroid sex hormones on VSMC, including experiments to: (a) identify steroid sex hormone-induced changes in gene expression, and (b) explore "cross-talk" between cell surface receptor and steroid sex hormone receptor-mediated pathways. Cells from different vascular beds and from normal and diseased tissues will be studied using VSMC cultured from human saphenous vein, mammary artery, aorta, and coronary atherectomy specimens. These studies have important implications for understanding the pathophysiology and treatment of CAD in both men and women, and are therefore of central relevance to cardiovascular biology.